SAMe shows promise in liver cancer prevention

The August, 2009 issue of the journal Hepatology published the discovery of researchers at the University of Southern California (USC) of a role for S-adenosylmethionine (SAMe) in the prevention of hepatocellular carcinoma (HCC), or primary liver cancer.

In one experiment, Shelly Lu, MD, of USC’s Keck School of Medicine and her associates injected rats with liver cancer cells, which resulted in 1 centimeter tumor formation in 80 percent of the animals after two weeks. Beginning 24 hours after the injection, 6 rats received 150 milligrams per kilogram intravenous SAMe and another 6 received a control substance daily for 11 days. At the end of the treatment period, the animals were examined for tumor presence and size. While two of the rats treated with SAMe were found to have small tumors, much larger tumors were discovered in four of the animals that received the control substance.

In another experiment, rats with established tumors of at least 1 centimeter in size were given intravenous SAMe for 24 days. Examination of animals determined that SAMe was not effective in halting the growth of these tumors, and that, although plasma SAMe remained elevated, liver SAMe levels were only 30 percent above the control levels at the end of the study. In their discussion of the results, the scientists proposed a compensatory response by the liver to metabolize SAMe in order to prevent its accumulation.

“The observation that SAMe failed to exert any therapeutic effect in already established HCC is disappointing.” Dr Lu stated. But whether SAMe can be effective in treating HCC in man remains unclear because this compensatory mechanism may not work properly in human HCC. Nevertheless, effectiveness of SAMe in chemoprevention of human HCC deserves study now.”

Epidemiological studies have associated increased genistein intake with a reduction in metastatic prostate cancer rates. Although genistein has been shown to block the activation of a proinvasion pathway known as p38 mitogen-activated protein kinase (MAPK), genistein’s specific upstream target for inhibiting cell invasion had been unknown.

Previous research demonstrated that p38 MAPK increases matrix metalloproteinase-2 (MMP-2) expression and cell invasion. Matrix metalloproteinase-2 has been found to be elevated in invasive prostate cancer tissue. Using six prostate cell lines, Li Xu, MD, PhD, and Raymond C. Bergan, MD, of Northwestern’s Department of Medicine and their associates found that genistein binds to the active site of a protein upstream from p38 MAPK known as mitogen-activated protein kinase 4 (MEK4), which, when overexpressed, increased matrix metalloproteinase-2 expression and cell invasion in all lines. Enzymatic assay confirmed MEK4 activity inhibition by genistein.

In a randomized trial of 24 prostate cancer patients, matrix metalloproteinase-2 levels in normal prostate epithelial cells were found to be lower in genistein-treated patients than in those who did not receive genistein. “We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of matrix metalloproteinase-2 transcripts in normal prostate cells from prostate cancer-containing tissue,” the authors write. “This finding supports the possibility that destabilization of a premalignant field can potentially be prevented by therapeutically targeting cell motility processes that are linked to cancer, as has been proposed previously.”

—D Dye

July 27, 2009

Greater fiber intake associated with lower breast cancer risk

An article published online on July 22, 2009 in the American Journal of Clinical Nutrition adds evidence to the possibility of a protective association for increased fiber intake against the risk of breast cancer, however, findings from the study suggest that the mechanisms involved may be different from what had previously been hypothesized.

For their research, a team from the National Cancer Institute evaluated data from 185,598 postmenopausal women who participated in the National Institutes of Health-AARP Diet and Health Study. Dietary questionnaires completed upon enrollment were analyzed for the amount of fiber consumed from grains, fruit, vegetables and beans.

Over an average of 7 years of follow up, 5,461 cases of breast cancer were diagnosed, of which the estrogen and progesterone receptor status was known for 3,341. Women whose fiber intake was among the top one-fifth of participants were found to have a 13 percent lower risk of breast cancer than those in the lowest fifth. However, when the risk was examined by type of cancer, women whose tumors were estrogen and progesterone receptor positive whose fiber intake was among the top 20 percent experienced only a 5 percent risk reduction, while those with estrogen and progesterone receptor negative tumors had a 44 percent lower risk.

The fact that vegetarian women have greater excretion of estrogens and lower estrogen levels than nonvegetarians led earlier researchers to hypothesize that increased dietary fiber might reduce the risk of breast cancer. However, fiber’s ability to help control insulin and insulin-like growth factors, which have more recently been related to breast cancer risk, could be a more important mechanism.

“Our findings suggest that dietary fiber can play a role in preventing breast cancer through nonestrogen pathways among postmenopausal women,” the authors conclude.

—D Dye

July 24, 2009

NAC may help reduce compulsive behaviors

In the July, 2009 issue of the American Medical Association journal Archives of General Psychiatry, researchers from the University of Minnesota School of Medicine report that supplementing with the amino acid N-acetylcysteine (NAC) helps reduce trichotillomania, a condition in which women, men and even pets engage in compulsive hair pulling that results in noticeable hair loss. "Trichotillomania is characterized by the following diagnostic criteria: the recurrent pulling out of one's hair, which results in noticeable hair loss; an increasing sense of tension immediately before pulling out the hair or when attempting to resist the behavior; and pleasure, gratification or relief when pulling out hair," the authors reveal in their introduction to the article. "Psychosocial problems are common in individuals with trichotillomania and include significantly reduced quality of life, reduced work productivity and impaired social functioning."

Acting on previous findings of an ability for N-acetylcysteine to help control urges such as those associated with cocaine and gambling, Jon E. Grant, JD, MD, MPH and his associates randomized 5 men and 45 women to receive 1200 to 2400 milligrams per day of NAC or a placebo for 12 weeks. While 16 percent of the placebo group experienced improvement, 56 percent of those who received NAC reported being “much or very much” improved. Progress was noted as early as after 9 weeks of treatment, and no adverse effects were observed. The benefit associated with NAC was greater than that provided by medications prescribed for the condition, and comparable to results achieved with cognitive behavior therapy.

N-acetylcysteine appears to work by affecting the glutamate system, which is the largest neurotransmitter system in the brain. "Pharmacologic modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors,“ the authors conclude.

—D Dye

July 22, 2009

Heart healthy habits help the head

The Alzheimer's Association 2009 International Conference on Alzheimer's Disease held this month in Vienna was the site of presentations concerning the benefits of a heart-healthy diet and exercise in lowering the risk of age-related cognitive decline.

Utah State University Assistant Professor of Nutrition Nancy Wengreen, RD, PhD reported the outcome of a study of 3,831 men and women aged 65 years and older which found that greater adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with better cognitive function over an 11 year period. Participants with dietary scores that were among the top 20 percent of subjects had better cognitive function test scores at the beginning of the study as well as at the end of follow-up compared to those whose dietary scores were low. Of nine dietary components evaluated, four were independently associated with cognitive function scores. “Our results suggest that including whole grains, vegetables, low-fat dairy foods, and nuts in one's diet may offer benefits for cognition in late life," Dr Wengreen revealed."

In a second presentation, University of California, San Francisco assistant Professor of Psychiatry Deborah E. Barnes, PhD, MPH and colleagues evaluated the effect of changes in physical activity on the cognitive function of 3,075 participants in the Health, Aging and Body Composition Study. "We found that older adults who were sedentary throughout the study had the lowest levels of cognitive function at the beginning and experienced the fastest rate of cognitive decline," Dr Barnes reported. "Cognitive decline also was faster in those whose physical activity levels consistently declined during the study period."

"We can't do anything about aging or family history,” concluded William Thies, PhD, who is Chief Medical and Scientific Officer at the Alzheimer's Association, “But research continues to show us that there are lifestyle decisions we all can make to keep our brains healthier, and that also may lower our risk of memory decline as we age."

—D Dye

July 20, 2009

Greater fish intake could help reduce global dementia burden

Eating more fish and less meat could help reduce the impact of dementia that currently afflicts 24 million individuals worldwide, according to a report published in the August, 2009 issue of the American Journal of Clinical Nutrition.

Emiliano Albanese of King’s College London along with a team of international researchers evaluated data from 14,960 men and women aged 65 and older residing in China, India, Cuba, the Dominican Republic, Venezuela, Mexico and Peru. Participant interviews obtained information on dementia diagnoses, sociodemographic characteristics and dietary intake. Weekly fish and meat intake were categorized as “Never,””Some days,” or “Most/every day.”

With the exception of India, greater fish intake was correlated with a lower prevalence of dementia in all countries, with the lowest reduction in risk for each increase in fish consumption category occurring in China. Combined analysis of data from all of the countries included in the study found a 19 percent lower risk of dementia with each increase in fish consumption category, and a 19 percent elevation in risk for each increase in meat consumption category.

“We showed for the first time that a statistically significant trend toward a lower prevalence of dementia among those with higher dietary fish intake in large population-based samples of older people living in 5 countries in Latin America, China, and India,” the authors write. “To our knowledge, this is the largest population-based study on this topic to date from either developing or developed country samples.”

“Our results extend findings on the associations of fish and meat consumption with dementia risk to populations in low and middle-income countries and are consistent with mechanistic data on the neuroprotective actions of omega-3 (n–3) long-chain polyunsaturated fatty acids commonly found in fish,” they conclude.

—D Dye

July 17, 2009

Vitamin D and curcumin could help rid the brain of Alzheimer's plaques

Scientists at the University of California Riverside and Los Angeles report that a combination of vitamin D3 and a synthetic form of curcumin could help remove amyloid beta from the brains of Alzheimer’s disease patients. The research was published in the July, 2009 issue of the Journal of Alzheimer's Disease.

Amyloid beta accumulates in the brain when the innate immune system fails to clear it. The substance forms the plaques that, along with neurofibrillary tangles, characterize Alzheimer’s disease. For their research, Dr Milan Fiala of UCLA’s David Geffen School of Medicine and his associates tested the effects vitamin D and curcuminoids, which are synthetic forms of the compound curcumin, on white blood cells known as monocytes derived from nine men and women with Alzheimer’s disease, one man with mild cognitive impairment, and three control subjects. Monocytes are immune system cells that transform into macrophages which travel through the body to consume waste products, including amyloid beta.

The team found that vitamin D3 significantly stimulated phagocytosis and clearance of amyloid beta while protecting against programmed cell death. Specific curcuminoids increased amyloid beta clearance by enhancing its surface binding to macrophages.

Synthetic forms of curcumin were tested in the current experiments due to challenges with natural curcumin’s ability to absorb and remain stable. Nevertheless, previous research conducted by the team found that not all Alzheimer’s disease patients respond to curcuminoids.

"We hope that vitamin D3 and curcumin, both naturally occurring nutrients, may offer new preventive and treatment possibilities for Alzheimer's disease," stated Dr Fiala. "Since vitamin D and curcumin work differently with the immune system, we may find that a combination of the two or each used alone may be more effective — depending on the individual patient."

—D Dye

July 15, 2009

Curcumin may help protect against hormone replacement breast cancer risk

In an article scheduled for publication in the journal Menopause, scientists at the University of Missouri reveal that curcumin, the active compound in the spice turmeric, could help prevent one type of breast cancer in women who use estrogen and progestin hormone replacement therapy. The combined oral use of these hormones has been associated with an increased incidence of breast cancer among older women, although estrogen alone was not found to be associated with an increased risk of the disease.

Salman Hyder, who is a professor of biomedical sciences at the University of Missouri’s College of Veterinary Medicine and Dalton Cardiovascular Research Center, and his colleagues tested the effect of curcumin in an animal model of progestin-driven breast cancer and found that the compound delayed the appearance of tumors and reduced their incidence. Additionally, mammary glands of animals that received curcumin were protected against the appearance of morphological abnormalities. The researchers found that curcumin inhibited the progestin-induced secretion of vascular endothelial growth factor (VEGF), which aids in the formation of tumor blood vessels.

"Approximately 6 million women in the United States use hormone replacement therapy to treat the symptoms of menopause," Dr Hyder observed. "This exposure to progestin will predispose a large number of postmenopausal women to future development of breast cancer. The results of our study show that women could potentially take curcumin to protect themselves from developing progestin-accelerated tumors."

"Curcumin and other potential antiangiogenic compounds should be tested further as dietary chemopreventive agents in women already exposed to hormone replacement therapy containing estrogen and progestin in an effort to decrease or delay the risk of breast cancer associated with combined hormone replacement therapy," Dr Hyder recommended.

—D Dye

July 13, 2009

Thymus maintained in modified mice

In the July 7, 2009 issue of the Proceedings of the National Academy of Sciences, researchers at the University of Pittsburgh report that mice genetically modified to lack a specific enzyme live longer and maintain an intact thymus gland throughout their lives. The thymus gland plays an important role in immune function by producing T cells that fight infection, however, the gland normally shrinks with age in mammals.

University of Pittsburgh School of Medicine associate professor of pediatrics and immunology Abbe de Vallejo, PhD and colleagues used a mouse model developed by report coauthor Cheryl Conover , PhD of the Mayo Clinic. These animals lack an enzyme known as pregnancy-associated plasma protein A (PAPPA) that controls the availability in the tissues of insulin-like growth factor (IGF), which promotes cell division. Although IGF is necessary for normal growth during youth, it has also been associated with inflammation, cardiovascular disease and the growth of tumors. In “PAPPA-knockout” mice, life span is increased by 30 percent compared with non-modified mice, and the animals develop fewer spontaneous tumors.

In the current research, the deletion of the gene for PAPPA maintained enough IGF to sustain T cell production without consuming precursor cells, which prevented the thymus from atrophying. "These findings give us hope that we may one day have the ability to restore the function of the thymus in old age, or perhaps by intervening at an early age, we may be able to delay or even prevent the degeneration of the thymus in order to maintain our immune defenses throughout life," Dr de Vallejo stated. "Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune protection throughout life. This study has profound implications for the future study of healthy aging and longevity."

An advance access article published on May 22, 2009 in the American Journal of Epidemiology revealed the results of a meta-analysis conducted by Spanish researchers which determined that higher levels of the body's antioxidant enzymes correlate with a lower risk of coronary heart disease. The enzymes defend against oxidative stress, which is characterized in atherosclerosis by the oxidation of lipids and proteins in the vascular wall, a process that is considered to be an initial step in heart disease. Oxidative stress is also involved in endothelial dysfunction, which plays a major role in the disease.

For their analysis, Dr Maria-Isabel Covas, of the Cardiovascular Risk and Nutrition Research Group in Barcelona and her colleagues selected 42 case-control studies and 3 prospective studies that provided information concerning levels of the enzymes superoxide dismutase, catalase and glutathione peroxidase, and coronary heart disease outcomes including fatal heart disease, nonfatal heart attack, or angina. Pooled analysis of the data found a reduced risk of heart disease associated with higher levels of each enzyme compared with lower levels. The risk associated with a 1-standard-deviation increase (a measure of variance from average values) in glutathione peroxidase was 49 percent lower, while those associated with superoxide dismutase and catalase were 52 percent and 68 percent lower.

According to the authors, the relationship between antioxidant enzyme levels and heart disease risk had not been previously evaluated. While the analysis determined strong inverse associations between antioxidant enzyme levels and coronary heart disease outcomes, it is not known whether lower enzyme levels are a causative factor or a result of the increased oxidative stress induced by a coronary event or subclinical disease. The authors recommend large, prospective cohort studies to further evaluate the association.

—D Dye

July 08, 2009

Drug extends lives of old mice

In an article published on July 8, 2009 in the journal Nature, scientists from three U.S. research centers report that rapamycin, a compound discovered on Easter Island that has diverse medical uses, extends the life span of mice when given in old age.

Researchers at the University of Texas Health Science Center’s Institute of Biotechnology and Barshop Institute for Longevity and Aging Studies, the University of Michigan, and the Jackson Laboratory in Bar Harbor, Maine collaborated on the current study. The team intended to give rapamycin to mice beginning at 4 months of age, however, the compound proved to be unstable in food and in the animals’ digestive tracts. By the time the drug was reformulated to bypass the stomach and break down in the intestine, the animals were 20 months old, the equivalent of age 60 in humans. The scientists decided to go ahead with the experiment despite the animals’ advanced age and were surprised by the results. Mice that received rapamycin were found to experience an extension of 28 to 38 percent in life expectancy, an effect greater than that which would occur in humans if heart disease and cancer did not exist. The drug’s mechanism appears to be similar to that of calorie restriction.

"I did not think that it would work because the mice were too old when the treatment was started," stated Barshop Institute director Arlan G. Richardson, PhD. "Most reports indicate that calorie restriction doesn't work when implemented in old animals. The fact that rapamycin increases lifespan in relatively old mice was totally unexpected."

"I've been in aging research for 35 years and there have been many so-called 'antiaging' interventions over those years that were never successful," Dr Richardson added. "I never thought we would find an antiaging pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that."

—D Dye

July 06, 2009

Caffeine reduces Alzheimer’s signs in mouse model

Articles published online on June 5, 2009 in the Journal of Alzheimer's Disease reveal that an amount of caffeine equivalent to 5 cups of coffee in humans reversed memory loss in mice bred to develop Alzheimer’s disease, in addition to lowering blood and brain levels of amyloid-beta, the substance that accumulates in the brains of human Alzheimer’s disease patients.

Previous research conducted by the team demonstrated that caffeine was protective against the development of Alzheimer’s disease in these animals, yet it was not known what effect the compound would have on mice that already showed signs of the disease. In one report, Gary Arendash, PhD his associates at the University of South Florida’s Florida Alzheimer’s Disease Research Center reveal that 4 to 5 weeks of caffeine treatment resulted in improved working memory in 18 to 19 month old mice, while untreated animals continued to decline. Treated mice also experienced a reduction in brain amyloid beta deposits. In the second article, the team reported that short term caffeine administration to both young and old transgenic mice rapidly reduced amyloid beta levels in the brain and plasma. Long term administration provided similar effects.

"The new findings provide evidence that caffeine could be a viable 'treatment' for established Alzheimer's disease, and not simply a protective strategy," Dr Arendash commented. "That's important because caffeine is a safe drug for most people, it easily enters the brain, and it appears to directly affect the disease process."

"These are some of the most promising Alzheimer's mouse experiments ever done showing that caffeine rapidly reduces beta amyloid protein in the blood, an effect that is mirrored in the brain, and this reduction is linked to cognitive benefit," stated Florida Alzheimer’s Disease Research Center Director Huntington Potter, PhD. "Our goal is to obtain the funding needed to translate the therapeutic discoveries in mice into well-designed clinical trials."

—D Dye

July 03, 2009

Decreased stomach acid might be linked to osteoporosis

In an article published in the June, 2009 issue of Nature Medicine, German researchers report an association between defective gastric acid secretion and reduced bone mineralization in mice.

The predominant mineral in bone is calcium, whose normal levels in the blood are maintained in a process known as homeostasis. When blood levels are low, parathyroid hormone stimulates the small intestine to absorb dietary calcium and cells known as osteoclasts to mobilize calcium from the bone. Osteoclasts mobilize bone calcium by secreting hydrochloric acid via a proton pump and chloride channel to release calcium into the blood stream, thereby maintaining calcium homeostasis. Increased osteoclast activity causes osteoporosis, a condition characterized by decreased bone density, which is the opposite of that which occurs in osteopetrosis, a potentially lethal disease caused by a mutation that prevents osteoclasts from breaking down or resorbing bone during development, leading to excessive bone density.

In the current research, mice that were deficient in an enzyme needed for osteoclast activity showed signs of osteopetrosis but did not have low blood levels of calcium, demonstrating that osteoclast dysfunction alone does not affect calcium homeostasis. Another group of mice bred to lack a gene (Cckbr) needed for gastric acid secretion had mildly low levels of calcium, but high parathyroid hormone levels and large numbers of osteoclasts, which, because they mobilize calcium from bone, apparently prevented the mineral from becoming severely low. The team showed that calcium gluconate was more effective than calcium carbonate at treating the osteoporosis that occurred in these animals, presumably, as noted by Brendan F. Boyce in an accompanying editorial, because it dissolves better at a higher pH. “These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice,” the authors conclude.

According to Dr Boyce, the current findings suggest that calcium deficiency associated with low stomach acid can induce osteoclasts to degrade bone enough to result in osteoporosis, and asks whether the approximate one-third of older individuals who are deficient in stomach acid could represent the majority of those who develop the disease.

In the July, 2009 issue of the journal Nutrition and Cancer, researchers at the Veterans Administration Medical Center, Karmanos Cancer Center and Wayne State University in Detroit report that a combination of curcumin and resveratrol showed greater inhibitory effects against cancer cells compared with either agent used alone.

Adhip P. N. Majumdar and colleagues incubated human colon cancer cells with varying concentrations of curcumin, resveratrol or both agents combined. Untreated cells served as controls. Although both agents inhibited cell growth dose-dependently, the combination of curcumin and resveratrol elicited a greater effect than either extract used separately, suggesting a synergistic benefit.

Further experimentation showed that the synergism was effective in both p53 positive and p53 negative colon cancer cells. While curcumin or resveratrol alone inhibited the growth of these cells by 15 to 30 percent, the combination resulted in a 40 percent inhibition compared to the control cells.

In another experiment in which colon cancer cells were grated into mice, the combination of resveratrol and curcumin once again was associated with greater tumor growth inhibition than either therapy alone. The number of cells undergoing apoptosis in response to the curcumin/resveratrol combination was found to be double that of treatment with either agent by itself. Activation of the transcription factor nuclear factor kappa-beta (NF-kB), which stimulates the transcription of genes involved in cell survival, was similarly decreased by the administration of curcumin and resveratrol.

“Our data show that the combination therapy of curcumin and resveratrol is highly effective in inhibiting the growth of colon cancer cells in vitro and in vivo, which could be attributed to inhibition of proliferation and stimulation of apoptosis resulting from attenuation of nuclear NF-kb activity,” the authors write. “The combination of curcumin and resveratrol could be an effective preventive/therapeutic strategy for colon cancer,” they conclude.

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